tbuckley/cabot-search huggingface dataset:
KCNJ15 deficiency promotes drug resistance via affecting the function of lysosomes
Authors: Xinbo Qiao, Yixiao Zhang, Zhan Zhang, Nan Niu, Haonan Li, Lisha Sun, Qingtian Ma, Jiawen Bu, Jinchi Liu, Guanglei Chen, Jinqi Xue, Yongliang Yang, Caigang Liu
Journal: Asian Journal of Pharmaceutical Sciences (2023)

The altered lysosomal function can induce drug redistribution which leads to drug resistance and poor prognosis for cancer patients. V-ATPase, an ATP-driven proton pump positioned at lysosomal surfaces, is responsible for maintaining the stability of lysosome. Herein, we reported that the potassium voltage-gated channel subfamily J member 15 (KCNJ15) protein, which may bind to V-ATPase, can regulate the function of lysosome. The deficiency of KCNJ15 protein in breast cancer cells led to drug aggregation as well as reduction of drug efficacy. The application of the V-ATPase inhibitor could inhibit the binding between KCNJ15 and V-ATPase, contributing to the amelioration of drug resistance. Clinical data analysis revealed that KCNJ15 deficiency was associated with higher histological grading, advanced stages, more metastases of lymph nodes, and shorter disease free survival of patients with breast cancer. KCNJ15 expression level is positively correlated with a high response rate after receiving neoadjuvant chemotherapy. Moreover, we revealed that the small molecule drug CMA/BAF can reverse drug resistance by disrupting the interaction between KCNJ15 and lysosomes. In conclusion, KCNJ15 could be identified as an underlying indicator for drug resistance and survival of breast cancer, which might guide the choice of therapeutic strategies.
Understanding statistical hypothesis testing
Authors: P. Sedgwick
Journal: BMJ (2014)

Adaptor MyD88 has a pivotal role in TLR and IL-1R signaling and is involved in mediating excessive inflammation. MyD88 is composed of a death domain and a Toll/IL-1R domain connected by an intermediary domain (INT). The alternatively spliced form of MyD88 lacking the INT prevents signaling through MyD88-dependent TLRs. We designed a peptide from the INT and showed that it inhibits TLR4 activation by LPS when linked to a cell-penetrating peptide. As a new approach for the delivery of signaling-inhibitory peptides, INT peptide acylation also provided efficient cell translocation and inhibition of activation. We determined that INT peptide targets IL-1R–associated kinase 4. Furthermore, MyD88 mutant and molecular modeling refines the MyD88– IL-1R–associated kinase 4 interaction model based on the Myddosome structure. In addition to TLR4, INT peptide also inhibited TLR5, TLR2, TLR9, and IL-1R signaling but not TLR3, which uses Toll/IL-1R domain-containing adapter inducing IFN-β signaling adaptor. Inhibition of signaling in murine and human cells was observed by decreased NF-κB activation, cytokine mRNA synthesis, and phosphorylation of downstream kinases. In the endotoxemic mouse model, INT peptide suppressed production of inflammatory cytokines and improved survival, supporting therapeutic application of INT peptides for the suppression of inflammatory conditions mediated by MyD88.
POS0941 SYSTEMIC SCLEROSIS IS A RISK FACTOR OF INCIDENT PSORIASIS: RESULTS FROM A NATIONWIDE COHORT STUDY
Authors: O. C. Kwon, K. D. Han, M. C. Park
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Co-existing psoriasis (PsO) in patients with systemic sclerosis (SSc) has been reported. However, it is unclear whether SSc contributes as a risk factor for development of PsO. <h3>Objectives</h3> We aimed to assess whether SSc is associated with the risk of incident PsO. <h3>Methods</h3> From the Korean National Health Insurance Service database, 4,933 patients with SSc and 24,665 age- and sex-matched controls were selected. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident PsO were estimated using multivariable Cox proportional hazard models adjusted for known risk factors of PsO. Further, we selected individuals whose health check-up data were available (2,355 patients with SSc and 11,775 age- and sex-matched controls). In this population, we further adjusted for additional risk factors of PsO using the health check-up data. <h3>Results</h3> In the analysis of 4,933 patients with SSc and 24,665 age- and sex-matched controls, incidence rates of PsO in patients with SSc and controls were 10.26 and 3.20 per 1,000 person-years, respectively. After adjusting for risk factors of PsO, patients with SSc had a significantly higher risk of incident PsO (adjusted HR: 3.055 [95% CI: 2.597, 3.594]). Moreover, in the analysis of individuals who had health check-up data, additional risk factors of PsO were further adjusted; the result also showed that patients with SSc have a significantly higher risk of incident PsO (adjusted HR: 2.820 [95% CI: 2.207, 3.603]). <h3>Conclusion</h3> In this large cohort study, SSc was associated with a 3-fold higher risk of incident PsO than controls, independent of known risk factors of PsO. This observation advances our knowledge by showing that a risk relationship exists between SSc and PsO, beyond a simple co-existence between the two conditions. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
POS0899 SPECIFICITY OF SALIVARY GLAND ULTRASOUND IN THE DISCRIMINATION OF PRIMARY SJOGREN’S SYNDROME FROM UNDIFFERENTIATED CONNECTIVE TISSUE DISEASES
Authors: M. Djennane, T. Arezki, S. Slimani, H. Imene, A. Ifticene
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Recently, compelling data have been published on the value of salivary gland ultrasound (SGUS) in differentiating between primary Sjögren's Syndrome (SS) from nonimmune-mediated sicca syndrome. Limited data are available regarding the diagnostic accuracy of SGUS to distinguish SS from undifferentiated connective tissue diseases associated with sicca syndrome. <h3>Objectives</h3> The aim of this study was to evaluate the power of SGUS to distinguish patients with SS from those with xerostomia and/or xerophthalmia and suffering from undifferentiated connective tissue diseases. <h3>Methods</h3> Our cross-sectional study consecutively recruited 95 patients with either SS (according to the American European Consensus Group criteria) or undifferentiated connective tissue diseases associated with sicca syndrome. Immunological assessment and salivary gland biopsies were performed in all patients. Ultrasonography of the parotid and submandibular glands on both sides were assessed for size, parenchymal echogenicity, and inhomogeneity, by the same blinded rheumatologist. A second ultrasound reading was performed blinded by another rheumatologist, with inter-observer Kappa calculation. Ultrasound abnormalities of the salivary glands were graded according to the OMERACT score ranging from 0 to 3 (threshold ≥2). <h3>Results</h3> The study included 95 patients; 51 with SS and 44 with undifferentiated connective tissue disease. Patients with SS showed a higher SGUS score compared with those with rheumatism with sicca syndrome [mean 1.69 (SD=1.17) versus 0.18 (SD= 0.44), P &lt; 0.0001]. The SGUS threshold showed a sensitivity of 60%, a specificity of 98%, a positive predictive value of 97% and a negative predictive value of 67% for the diagnosis of SG. A significant correlation was also found between the SGUS score and the minor salivary gland biopsy/focus score (r=0.64, P&lt;0.0001). Finally, the inter-observer Kappa coefficient ranged from 0.61 to 0.70. <h3>Conclusion</h3> Our study confirmed the good sensitivity and high specificity of SGUS in differentiating SS from other undifferentiated connective tissue diseases with sicca syndrome. <h3>Reference</h3> [1]De Vita S, Lorenzon G, Rossi G, Sabella M, Fossaluzza V. Salivary gland echography in primary and secondary Sjogren's syndrome. Clin Exp Rheumatol 1992;10:351 6. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
POS0956 GENETIC EVIDENCE REVEALS CAUSAL LINK BETWEEN RHEUMATOID ARTHRITIS AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE
Authors: M. R. Chen, K. X. Yao, Y. X. Yang, J. Qiao, S. X. Zhang, C. Wang, X. Li
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Observational studies have extensively investigated the association between rheumatoid arthritis (RA) and atherosclerotic cardiovascular disease (ASCVD). However, the direction of the causal effect between the two remains controversial, making it difficult to assess its clinical applicability. <h3>Objectives</h3> This study aimed to test whether RA is causally associated with ASCVD and its directionality using Mendelian randomization (MR). <h3>Methods</h3> A two-sample Mendelian randomization (TSMR)1 analysis was systematically performed to explore the causal relationship between RA and ASCVD. Single nucleotide polymorphisms (SNPs) associated with RA were selected from a large genome-wide association study (GWAS) of 58284 European individuals. Genetic association estimates for ASCVD were obtained from large joint studys(ISGC/MEGASTROKE consortium and CARDIoGRAMplusC4D), the UKBB and Finngen consortium.Preliminary analysis was performed using inverse variance weighting (IVW) and MR- egger regression. Cochran’s Q test and MR multiplicity residuals and outliers (MR- presso) were used to detect and correct for the effects of horizontal multiplicity to confirm the accuracy and robustness of our results. <h3>Results</h3> Positive causal associations were observed RA and risk of coronary artery disease (CAD) in Coronary Artery Disease GenomeWide Replication and Meta-analysis plus The Coronary Artery Disease (CARDIoGRAMplusC4D) (OR 1.0477; 95% CI, 1.0028-1.0945; P=0.037). Furthermore, UKBB (OR 1.0011; 95% CI, 1.0001-1.0022; P=0.034), and Finngen consortium (OR 1.0278; 95% CI, 1.0016-1.0547; P=0.038)also provide the same results. Important evidence for the association of RA with the higher risk of peripheral artery disease (PAD) in the Finngen consortium (OR 1.0409; 95% CI, 1.0086-1.0743; P=0.013) was found but there was no causal effect in UKBB (OR 1.0002, 95% CI: 1.0000-1.0005; P=0.097). There was no evidence of the association between RA and stroke outcomes (P &gt; 0.05). <h3>Conclusion</h3> MR studies provide suggestive evidence that RA increases the risk of CAD, while inconclusive evidence between RA and PAD suggests that improving the underlying RA risk may prevent cardiovascular disease. Otherwise, we found no evidence that RA increases risk factors for stroke. <h3>Reference</h3> [1]Pierce BL, Burgess S. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. <i>American journal of epidemiology</i> 2013;178(7):1177-84. doi: 10.1093/aje/kwt084 [published Online First: 2013/07/19] <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
POS0882 SCREENING/REFERRAL STRATEGIES FOR THE EARLY RECOGNITION OF PSA AMONG PATIENTS WITH PSORIASIS: RESULTS OF A GRAPPA SURVEY
Authors: K. Song, L. Webb, L. Eder, O. Fitzgerald, N. Goel, P. Helliwell, A. Katz, J. F. Merola, C. Rosen, L. Coates, D. Poddubnyy
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Diagnostic delay in psoriatic arthritis (PsA) is associated with poorer outcomes, and early screening/ referral strategies are important to reduce the delay. Implementation of early screening approaches demands cooperation between rheumatologists, dermatologists and primary care providers (PCPs). <h3>Objectives</h3> To explore the experiences of dermatologists and rheumatologists in the early recognition of PsA and suggest improvements to the current shared-care model. <h3>Methods</h3> A 24-question survey addressing referral strategies was constructed within GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) and sent to all members (n=927). Questions addressed the use of screening tools, interspecialty involvement in therapeutic decision making, and suggestions for earlier recognition. <h3>Results</h3> Surveys were completed by 113 rheumatologists from 37 countries (across six continents) and 26 dermatologists from 16 countries (across 4 continents), with a mean of 21.7 ± 10.7 and 18 ± 12.3 years experience, respectively. Of dermatologists, 81% use PsA-specific screening instruments. Conversely, rheumatologists reported that only 27% of patients referred to them from all sources had been assessed with screening tools. Across both specialties, "PEST" was reported to be the most used tool. Whilst dermatologists reported that 67% ± 28% of their suspected PsA cases were confirmed, rheumatologists felt ∼48% ± 24% of suspected PsA cases were confirmed. Both specialties (n=137) reported similar views regarding optimisation of the diagnostic process: 78% believed that the best approach involved combining patient-reported and physician-confirmed findings (see Figure 1A). Moreover, the education of PCPs was seen as the greatest priority to improve screening with 76% raising this as an unmet need (Figure 1B). <h3>Conclusion</h3> The survey indicated the current unmet needs in the early recognition of PsA. Accordingly, important areas to address include improving the use of validated screening instruments, increasing the education of community-based dermatologists and PCPs, and utilising a combination of patient-reported and physician-confirmed findings to identify patients with a high probability of PsA among those with psoriasis. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Kaiyang Song: None declared, Louisa Webb: None declared, Lihi Eder Shareholder of: UCB, Employee of: TrialSpark, Oliver FitzGerald: None declared, Niti Goel: None declared, Philip Helliwell: None declared, Arnon Katz: None declared, Joseph F. Merola: None declared, Cheryl Rosen: None declared, Laura Coates: None declared, Denis Poddubnyy: None declared.
POS0860 COMPARING THE EFFICACY OF THE BDMARD SWITCHER GROUP AND JAK CYCLER GROUP IN PATIENTS WITH RHEUMATOID ARTHRITIS WITH FAILURE TO THE JAK INHIBITORS
Authors: M. Yamasaki
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Patients benefiting from the advent of JAK inhibitors has increased in the treatment of rheumatoid arthritis(RA). However, it is also known that there are RA cases that do not respond sufficiently to JAK inhibitors(JAKi). In order not to increase the number of refractory rheumatoid arthritis cases, it is necessary to establish the following treatment methods for JAKi-resistant cases. <h3>Objectives</h3> We analyzed the efficacy of the bDMARD switcher group and the JAKi cycler group as the next treatment for JAKi- refractory cases. <h3>Methods</h3> Cases were recruited to SHin-yokohama Arthritis REgister (SHARE) between 2015 and 2022 (n=4,056). 347 Patients were diagnosed according to ACR/EULAR 2010 classification criteria and treated with JAKi. Efficacy analysis was evaluated by continuation rate and CDAI improvement rate. <h3>Results</h3> JAKi were administered to 347 patients for an average of 64.5 weeks. There were 75 cases (21.6%) who discontinued the JAKi due to insufficient effect. Of the cases in which JAKi were discontinued, 45 (60.0%) were in the bDMARD switcher group, 22 (29.3%) were in the JAK cycler group, and 8 (10.7%) were switched to csDMARD alone. The continuation rate of the next treatment in the bDMARD switcher group and the JAK cycler group was 77.8% and 89.0% at week 12, respectively, with no significant difference (Log-rank p=0.2806). The CDAI improvement rates in switcher group and the JAK cycler group were 43.5% and 46.2%, respectively, at week 12, with no significant difference (Wilcoxon p=0.6397). There was no significant difference in the CDAI improvement rate according to the treatment class and the number of b/tsDMARDs between the two groups (p&gt;0.05). CDAI improvement rate with each of following b/tsDMARs were TNFi=48.2%, IL-6i=30.0%, abatacept=42.4%, JAKi=49.9%. Especially for IL-6 inhibitors, 50.2% CDAI improvement rate was obtained when sarilumab was selected as the following DMARD. <h3>Conclusion</h3> JAK cycler, as well as bDMARD switcher, may be useful as the next treatment for patients who discontinue JAKi. <h3>Reference</h3> [1]Ann Rheum Dis. 2022 Sep 13;annrheumdis-2022-222835.doi: 10.1136/ard-2022-222835. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> MASAOMI YAMASAKI Speakers bureau: Lilly, Abbvie, Asahi-Kasei, Eisai,
POS0876 ASYMPTOMATIC HELL ENTHESITIS IN PSORIASIS PATIENTS: AN ULTRASOUND STUDY
Authors: R. Ben Aissa, S. Boussaid, S. Rekik, S. Rahmouni, S. Jemmali, K. Zouaoui, H. Srairi Sahli, M. Elleuch
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Enthesitis is a common clinical feature of psoriatic arthritis (PsA) especially in lower limb. Clinical screening for enthesitis in patients with psoriasis before developing PsA may be non-specific. Ultrasound has shown its value in the study of entheses. <h3>Objectives</h3> To asses heel entheses of asymptomatic psoriasis patients and healthy control using ultrasound. <h3>Methods</h3> We conducted a cross-sectional case-control study including psoriasis patients with no rheumatic symptoms and sex and age-matched healthy controls. We assessed the affected skin surface (SC) and the psoriasis severity score (PASI). Ultrasound evaluation of the calcaneal enthesis (CE) and the plantar fascia enthesis (PFE) was performed. Ultrasound abnormalities sought were: hypoechogenicity, enthesis thickening, bursitis, cortical erosion, calcification, enthesophyte, and presence of Doppler signal. <h3>Results</h3> A total of 76 patients (38 cases and 38 controls) were recruited with a mean age of 51.9±15 [19-76] years and male predominance (60%). On clinical examination, pressing pain was present at the CE and PFE in, respectively, 17.5% and 12.5% of psoriasis patients but with no significant difference comparing to controls (10% EC; 10% PFE respectively) (p=0.777; p=0.259 respectively). On ultrasound, 60% of psoriasis patients had at least one ultrasound abnormality at the CE versus 17.5% of controls (p&lt;0.001). The most observed ultrasound abnormalities at the CE were: enthesophyte (n=17), enthesis thickening (n=15), erosions (n=11) and hypoechogenicity (n=5). The PFE was less affected on ultrasound, presenting abnormalities in 42.5% of psoriasis patients versus 12.5% of controls (p=0.410). Erosions (n=13) and enthesis thickening (n=12) were the most observed abnormalities. The presence of ultrasound abnormalities at the PFE in psoriasis patients was correlated with age (p=0.012) and disease duration (p=0.015). Psoriasis severity according to SC and PASI was not associated with the presence of ultrasound abnormalities at CE (p=0.860; p=0.417 respectively) and PFE (p=0.399, p=0.156 respectively). <h3>Conclusion</h3> Our study showed that psoriasis patients could have asymptomatic heel enthesitis with greater involvement of the CE. Psoriasis patients need regular monitoring and screening for early symptoms of PsA. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
POS0854 DRUG RETENTION OF BIOLOGIC AND TARGETED SYNTHETIC DMARDS IN KOREAN SEROPOSITIVE RHEUMATOID ARTHRITIS (RA) PATIENTS: A REAL-WORLD SINGLE-CENTER RETROSPECTIVE STUDY
Authors: B. W. Lee, J. J. Lee, W. U. Kim
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Despite the approval of the new janus kinase inhibitors (JAKi) for rheumatoid arthritis (RA) treatment, the real world data on the drug effectiveness of biologic DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) including recently approved JAKi is scarce, especially in Asia. <h3>Objectives</h3> The purpose of this single center, retrospective study was to compare the short and long-term retention rates of b/tsDMARDs including recently approved JAKi in Korean seropositive RA patients. <h3>Methods</h3> This study was conducted with total 1,538 treatment courses of 1063 seropositive RA patients who started b/tsDMARDs between 2008 and 2020 at Seoul St. Mary's Hospital [adalimumab (ADA; n = 332), etanercept (ETN; n = 369), infliximab (IFX; n = 146), abatacept (ABT; n = 152), tocilizumab (TCZ; n = 299), tofacitinib (TOF; n = 136), and baricitinib (BAR; n = 104)]. Discontinuation after 1 year and 3 years from the first prescription of each drug was investigated. Kaplan–Meier estimates of time to discontinuation were conducted to compare the difference in drug retention rate for each drug in b/tsDMARDs-naïve and experienced group, respectively. Patient-level predictors for drug discontinuation were evaluated by a Cox proportional hazard model. <h3>Results</h3> Overall 1-year drug retention rate was as follows: from 60.1% of ADA to 90.0% of TOF in the b/tsDMARDs-naïve group &amp; from 55.2% of IFX to 84.8% of TOF in the b/tsDMARDs-experienced group. And 3-year drug retention rate was as follows: from 36.9% of IFX to 86.5% of TOF in the b/tsDMARDs-naïve group &amp; from 31.0% of IFX to 65.4% of TCZ in the b/tsDMARDs-experienced group. The drug discontinuation seems to be affected by several factors including previous treatment history, starting year, and specific type of b/tsDMARDs, and baseline level of erythrocyte sedimentation rate. <h3>Conclusion</h3> Compared to before 2015, the overall drug retention rate of b/tsDMARDs increased in Korean seropositive RA patients. TCZ and JAKi are as widely used as tumor necrosis factor-alpha inhibitors, and they were less often discontinued at 1 year and 3 years from the first prescription. Especially, drug with the highest 3-year retention rate was TOF in b/tsDMARDs-naïve group, and TCZ in b/tsDMARDs-experienced group. <h3>Reference</h3> [1]Smolen JS, Xie L, Jia B<i>, et al.</i> Efficacy of baricitinib in patients with moderate-to-severe rheumatoid arthritis with 3 years of treatment: results from a long-term study. <i>Rheumatology (Oxford</i>) 2021;60:2256-66. <h3>Acknowledgements</h3> No acknowledgements to declare. <h3>Disclosure of Interests</h3> None Declared.
POS0908 NAILFOLD CAPILLAROSCOPY FINDINGS OF INTERSTITIAL PNEUMONIA WITH AUTOIMMUNE FEATURES (IPAF)
Authors: S. H. Lee, H. K. Min, H. R. Kim
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Objectives: We evaluated nailfold capillaroscopy (NFC) of interstitial pneumonia with autoimmune features (IPAF) and compared it with that of patients with CTD-ILD and idiopathic interstitial pneumonia (IIP). <h3>Methods</h3> Patients with newly diagnosed as ILD were evaluated using NFC. Baseline demographic, clinical, serological, and high-resolution CT findings were collected. NFC was semi-quantitatively scored with six domains ranging from 0 to 18. In addition, the overall patterns (scleroderma/non-scleroderma patterns) were determined. <h3>Results</h3> A total of 81 patients (31 with CTD-ILD, 18 with IPAF, and 32 with IIP) were included. The non-specific interstitial pneumonia pattern was the most common ILD pattern in the CTD-ILD and IPAF groups, whereas the usual interstitial pneumonia pattern was the most common in the IIP group. The semi-quantitative score of the CTD-ILD group was higher than that of the IPAF or IIP groups (5.8 vs 4.2 vs 3.0, p &lt; 0.001, respectively). Giant capillaries and haemorrhages were more frequently present in the CTD-ILD and IPAF groups than in the IIP group. A scleroderma pattern was present in 27.8% of the IPAF group, whereas none of the IIP patients showed a scleroderma pattern. <h3>Conclusion</h3> NFC findings may be useful in classifying patients with ILD into CTD-ILD/IPAF/IIP. <h3>Reference</h3> [1]Fischer A, Antoniou KM, Brown KK, et al. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J 2015;46:976-987. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.